The present invention relates generally to novel organic synthetic methodology and its application for providing compounds that are useful as inhibitors of 11β-hydroxy steroid dehydrogenase type 1.
Hydroxysteroid dehydrogenases (HSDs) regulate the occupancy and activation of steroid hormone receptors via the interconvertsion between steroid hormones and its inactive form. For a recent review, see Nobel et al., Eur. J. Biochem. 2001, 268:4113-4125.
There exist numerous classes of HSDs. The 11-beta-hydroxysteroid dehydrogenases (11 β-HSDs) is an oxidoreductase whose oxidative component metabolises biologically active glucocorticosteroid (such as cortisol and corticosterone), to the inactive C-11 oxidised metabolites, cortisone and 11-dehydrocorticosternone. Ragosh, et al., J. Endocrinology, 1997, 155:171-180.
The isoform 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is expressed in liver, adipose tissue, brain, lung and other glucocorticoid tissue and is a potential target for therapy directed at numerous disorders that may be ameliorated by reduction of glucocorticoid action, such as diabetes, obesity and age-related cognitive dysfunction. Seckl, et al., Endocrinology, 2001, 142:1371-1376.
The 11β-HSD1 isoform is also present in pancreatic islet cells where it is implicated to play a role in controlling insulin release. Oppermann et al., J. Biological Chemistry, 2000, 275(45): 34841-34844. Glucocorticoid hormones such as cortisol (active form) and cortisone (inactive keto form) play a critical role in the regulation of carbohydrate metabolism. Increased levels of cortisol, promotes gluconeogenesis and inhibits insulin release. This results in high serum glucose levels characteristic of diabetic pathogenesis. Conversely, the known 11β-HSD1 inhibitor carbenoxolone reverses the inhibition of insulin release by cortisol in a dose dependent manner and further enhances insulin sensitivity. These observations indicate that 11β-HSD1 in pancreatic islet cells plays an important role in regulating glucocorticoid metabolism and release of insulin. Thus, 11β-HSD1 is an important enzyme target for the development of anti-diabetic therapeutic agents.
The C5-substituted 2-amino thiazolinones have been shown to be potent inhibitors of 11β-HSD1. In particular, 5S-2-(bicycle[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one, which is shown below, is a potent nanomolar inhibitor of this enzyme. Current synthetic routes to prepare this 2-aminothiazolone analog entail multiple steps and the use of high equivalents of an expensive chiral catalyst for the enantioselective addition of the isopropyl group to the C-5 atom of the parent 2-aminothiazolone.

There appears, therefore, a need for alternative synthetic methodology that would allow the facile and stereoselective preparation of 5S-2-(bicycle[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one and related compounds employing commercially available starting materials and small quantities of a chiral catalyst.